Nonsteroidal anti-inflammatory drugs (NSAIDs) are consumed by tens of millions worldwide. Although they relieve pain and inflammation, they also cause serious gastrointestinal and cardiovascular adverse effects and are thought to have caused hundreds of thousands of deaths. Despite enrolling more than 100,000 patients in randomized trials, we still do not know the NSAID of choice for patients with arthritis and heart disease or if NSAIDs differ in clinical efficacy. Here we propose a paradigm shifting, strategic approach to harvest benefit and manage risk by personalizing therapy with NSAIDs. An exploratory clinical study at scale will inform translational studies in which data from 5 systems - yeast, mammalian cells, zebrafish, mice and humans - will be integrated to create biochemical networks that inform and are refined by studies relating pharmacokinetics to pharmacodynamics. Hypotheses deriving from these studies will then be tested at scale in randomized prospective trials. This interdisciplinary strategy will deliver innovative tools and technologies, quantitative models and biomarkers of drug response and if successful will allow more rational prescription of NSAIDs to minimize risk and maximize benefit to individuals, creating a novel paradigm for the development and approval of drugs, the design of randomized trials and the treatment of chronic disease. PUBLIC HEALTH RELEVANCE: Drugs are prescribed based on detection of large average signals of effectiveness and hazard. This proposal attempts to refine the use of nonsteroidal anti-inflammatory drugs so that they are used in patients individually most likely to benefit and least likely to suffer adverse effects.